Abstract: Opioid abuse has escalated over the past several years into a national crisis presenting substantial health-care and socio-economic costs. Over-prescription of pain medications, such as hydrocodone and oxycodone, is thought to have strongly contributed to this abuse and its all-too-common slide into illicit heroin use. Reducing the liabilities of opioid-based analgesics may help stem this tide, and one manner by which this reduction could be performed is to enhance their analgesic potency, thereby decreasing the dose of opioid medication prescribed to an individual in pain. My preliminary findings suggest that Regulator of G Protein Signaling-12 (RGS12) may be a critical molecular component underlying the mechanisms by which these opioid analgesic drugs exert their effects. RGS12-deficient mice were found to have heightened hyperlocomotor and analgesic responses to acute morphine treatment. As RGS proteins like RGS12 are known as negative regulators of G protein-coupled receptor (GPCR) signal transduction, our hypothesis is that RGS12 deficiency leads to increased activity of the opioid-activated mu-opioid receptor (MOR); my initial data suggests that RGS12 loss does not lead to any increased MOR expression in the mouse brain. Given that RGS12 is expressed in MOR- dense mouse brain regions, such as the dorsal and ventral striatum, midbrain, and peripherally in dorsal root ganglia, there are several unanswered questions to be addressed to understand fully the role that RGS12 plays in behavioral responses to morphine and other opioid drugs. My first Aim is to establish the role of RGS12 in modulating opioid addictive potential, opioid withdrawal, and chronic opioid-use tolerance. My second Aim is to determine the specific neuronal circuitry and molecular signaling mechanisms involved in the enhanced opioidergic behaviors observed in the absence of RGS12 expression. Both of these aims will rely on behavioral and phenotypic analyses of two mouse models newly created in the Siderovski lab: both conventional (global) loss of RGS12 expression (Rgs12-/- mice) and conditional (Cre recombinase-dependent) loss of RGS12 expression (i.e., Rgs12fl/fl mice exposed to Cre expression via virion injection or transgenic driver cross-breeding). My overall goals are to validate RGS12 through these mouse strain-based studies as a novel molecular target within the processes of how opioid analgesia and opioid abuse are established and, more directly, to advance the idea that antagonizing RGS12 function as adjunctive pharmacotherapy alongside opioid analgesic use could help ameliorate the debilitating present epidemic of opioid abuse and addiction. My growth as a physician-scientist will be complemented by clinical training in the application of opioid analgesics and in the prevention and treatment of opioid addiction, via longitudinal engagements with practicing clinicians at WVU and the University of Pittsburgh actively engaged in pain management and in caring for persons recovering from Opioid Use Disorder via medication-assisted treatment and psychotherapy.